Skip to main content

Advertisement

SpringerLink
Log in

Molecular genetics of pancreatic intraepithelial neoplasia

  • Topics: Current understanding of precursors to pancreatic cancer
  • Published:
Journal of Hepato-Biliary-Pancreatic Surgery

Abstract

Background

Recent evidence suggests that noninvasive precursor lesions, classified as pancreatic intraepithelial neoplasia (PanIN), can progress to invasive pancreatic cancer. This review will discuss the major genetic alterations in PanIN lesions.

Methods

A comprehensive review of the literature was performed in order to find studies on the molecular profile of human PanIN lesions. In addition, recent publications on genetically engineered mouse models of preinvasive neoplasia and pancreatic cancers were reviewed.

Results

PanINs demonstrate abnormalities at the genomic (DNA), transcriptomic (RNA), and proteomic levels, and there is a progressive accumulation of molecular alterations that accompany the histological progression from low-grade PanIN-1A to high-grade PanIN-3 lesions. Molecular changes in PanINs can be classified as “early” (KRAS2 mutations, telomere shortening, p21WAF1/CIP1 up-regulation, etc.), “intermediate” (cyclin D1 up-regulation, expression of proliferation antigens, etc.), or “late” (BRCA2 and TP53 mutations, DPC4/SMAD4/MADH4 inactivation, etc.). All the genetic changes observed in PanINs are also found in invasive ductal adenocarcinomas, where they usually occur at a higher frequency. Genetically engineered mice expressing mutant Kras in the pancreas, with or without additional genetic alterations, provide a unique in vivo platform to study the pancreatic cancer progression model.

Conclusions

Molecular studies have been instrumental in establishing that PanIN lesions are the noninvasive precursors for invasive ductal adenocarcinomas. The availability of molecular date provides the basis for designing rational early detection strategies and therapeutic intervention trials before pancreatic neoplasms invade, with the intention of alleviating the dismal prognosis associated with this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. K Takaori RH Hruban A Maitra N Tanigawa (2004) ArticleTitlePancreatic intraepithelial neoplasia Pancreas 28 257–62 Occurrence Handle15084967 Occurrence Handle10.1097/00006676-200404000-00008

    Article  PubMed  Google Scholar 

  2. TP Yeo RH Hruban SD Leach RE Wilentz TA Sohn SE Kern et al. (2002) ArticleTitlePancreatic cancer Curr Probl Cancer 26 176–275 Occurrence Handle12399802 Occurrence Handle10.1067/mcn.2002.129579

    Article  PubMed  Google Scholar 

  3. GM Petersen RH Hruban (2003) ArticleTitleFamilial pancreatic cancer: where are we in 2003? J Natl Cancer Inst 95 180–1 Occurrence Handle12569133

    PubMed  Google Scholar 

  4. PR Srinivas BS Kramer S Srivastava (2001) ArticleTitleTrends in biomarker research for cancer detection Lancet Oncol 2 698–704 Occurrence Handle11902541 Occurrence Handle10.1016/S1470-2045(01)00560-5 Occurrence Handle1:CAS:528:DC%2BD3MXovVWntLo%3D

    Article  PubMed  CAS  Google Scholar 

  5. B Vogelstein KW Kinzler (1993) ArticleTitleThe multistep nature of cancer Trends Genet 9 138–41 Occurrence Handle8516849 Occurrence Handle10.1016/0168-9525(93)90209-Z Occurrence Handle1:STN:280:ByyB1MnovVE%3D

    Article  PubMed  CAS  Google Scholar 

  6. VG Vogel JP Costantino DL Wickerham WM Cronin (2003) ArticleTitleNational surgical adjuvant breast and bowel project update: prevention trials and endocrine therapy of ductal carcinoma in situ Clin Cancer Res 9 495S–501S Occurrence Handle12538506 Occurrence Handle1:CAS:528:DC%2BD3sXnt1yjuw%3D%3D

    PubMed  CAS  Google Scholar 

  7. SPL Hulst (1905) ArticleTitleZur kenntnis der genese des adenokarzinoms und karzinoms des pankreas Virchows Arch 180 288–316 Occurrence Handle10.1007/BF01968012

    Article  Google Scholar 

  8. AL Cubilla PJ Fitzgerald (1976) ArticleTitleMorphological lesions associated with human primary invasive nonendocrine pancreas cancer Cancer Res 36 2690–8 Occurrence Handle1277176 Occurrence Handle1:STN:280:CSmB3cfhs1Q%3D

    PubMed  CAS  Google Scholar 

  9. DS Klimstra DS Longnecker (1994) ArticleTitleK-ras mutations in pancreatic ductal proliferative lesions Am J Pathol 145 1547–50 Occurrence Handle7992857 Occurrence Handle1:STN:280:ByqD1crgt1A%3D

    PubMed  CAS  Google Scholar 

  10. S Kozuka R Sassa T Taki K Masamoto S Nagasawa S Saga et al. (1979) ArticleTitleRelation of pancreatic duct hyperplasia to carcinoma Cancer 43 1418–28 Occurrence Handle445339 Occurrence Handle10.1002/1097-0142(197904)43:4<1418::AID-CNCR2820430431>3.0.CO;2-O Occurrence Handle1:STN:280:CSaC1cbis10%3D

    Article  PubMed  CAS  Google Scholar 

  11. K Takaori Y Kobashi S Matsusue K Matsui T Yamamoto (2003) ArticleTitleClinicopathological features of pancreatic intraepithelial neoplasias and their relationship to intraductal papillary–mucinous tumors J Hepatobiliary Pancreat Surg 10 125–36 Occurrence Handle14505145 Occurrence Handle10.1007/s00534-003-0756-8

    Article  PubMed  Google Scholar 

  12. DJ Brat KD Lillemoe CJ Yeo PB Warfield RH Hruban (1998) ArticleTitleProgression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas Am J Surg Pathol 22 163–9 Occurrence Handle9500216 Occurrence Handle10.1097/00000478-199802000-00003 Occurrence Handle1:STN:280:DyaK1c7lvFymsA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  13. RH Hruban NV Adsay J Albores-Saavedra C Compton ES Garrett SN Goodman et al. (2001) ArticleTitlePancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions Am J Surg Pathol 25 579–86 Occurrence Handle11342768 Occurrence Handle10.1097/00000478-200105000-00003 Occurrence Handle1:STN:280:DC%2BD3M3ktV2kuw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  14. RH Hruban K Takaori DS Klimstra NV Adsay J Albores-Saavedra AV Biankin et al. (2004) ArticleTitleAn illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms Am J Surg Pathol 28 977–87 Occurrence Handle15252303 Occurrence Handle10.1097/01.pas.0000126675.59108.80

    Article  PubMed  Google Scholar 

  15. A Maitra N Fukushima K Takaori RH Hruban (2005) ArticleTitlePrecursors to invasive pancreatic cancer Adv Anat Pathol 12 81–91 Occurrence Handle15731576 Occurrence Handle10.1097/01.pap.0000155055.14238.25

    Article  PubMed  Google Scholar 

  16. B Vogelstein KW Kinzler (2004) ArticleTitleCancer genes and the pathways they control Nat Med 10 789–99 Occurrence Handle15286780 Occurrence Handle10.1038/nm1087 Occurrence Handle1:CAS:528:DC%2BD2cXmtFWrt7o%3D

    Article  PubMed  CAS  Google Scholar 

  17. C Caldas SE Kern (1995) ArticleTitleK-ras mutation and pancreatic adenocarcinoma Int J Pancreatol 18 1–6 Occurrence Handle7594765 Occurrence Handle1:CAS:528:DyaK2MXosF2gtrc%3D

    PubMed  CAS  Google Scholar 

  18. SR Hingorani DA Tuveson (2003) ArticleTitleRas redux: rethinking how and where Ras acts Curr Opin Genet Dev 13 6–13 Occurrence Handle12573429 Occurrence Handle10.1016/S0959-437X(02)00017-5 Occurrence Handle1:CAS:528:DC%2BD3sXmsFCjsQ%3D%3D

    Article  PubMed  CAS  Google Scholar 

  19. M Lohr G Kloppel P Maisonneuve AB Lowenfels J Luttges (2005) ArticleTitleFrequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis Neoplasia 7 17–23 Occurrence Handle15720814 Occurrence Handle10.1593/neo.04445

    Article  PubMed  Google Scholar 

  20. J Luttges A Diederichs MA Menke I Vogel B Kremer G Kloppel (2000) ArticleTitleDuctal lesions in patients with chronic pancreatitis show K-ras mutations in a frequency similar to that in the normal pancreas and lack unclear immunoreactivity for p53 Cancer 88 2495–504 Occurrence Handle10861425 Occurrence Handle10.1002/1097-0142(20000601)88:11<2495::AID-CNCR10>3.0.CO;2-B Occurrence Handle1:CAS:528:DC%2BD3cXktFGjs7Y%3D

    Article  PubMed  CAS  Google Scholar 

  21. L Laghi O Orbetegli P Bianchi A Zerbi V Di Carlo CR Boland et al. (2002) ArticleTitleCommon occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers Oncogene 21 4301–6 Occurrence Handle12082617 Occurrence Handle10.1038/sj.onc.1205533 Occurrence Handle1:CAS:528:DC%2BD38XkslKmtLs%3D

    Article  PubMed  CAS  Google Scholar 

  22. J Qian J Niu M Li PJ Chiao MS Tsao (2005) ArticleTitleIn vitro modeling of human pancreatic duct epithelial cell transformation defines gene expression changes induced by K-ras oncogenic activation in pancreatic carcinogenesis Cancer Res 65 5045–53 Occurrence Handle15958547 Occurrence Handle10.1158/0008-5472.CAN-04-3208 Occurrence Handle1:CAS:528:DC%2BD2MXltFemtb4%3D

    Article  PubMed  CAS  Google Scholar 

  23. SR Hingorani EF Petricoin A Maitra V Rajapakse C King MA Jacobetz et al. (2003) ArticleTitlePreinvasive and invasive ductal pancreatic cancer and its early detection in the mouse Cancer Cell 4 437–50 Occurrence Handle14706336 Occurrence Handle10.1016/S1535-6108(03)00309-X Occurrence Handle1:CAS:528:DC%2BD2cXitFOjsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  24. AJ Aguirre N Bardeesy M Sinha L Lopez DA Tuveson J Horner et al. (2003) ArticleTitleActivated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma Genes Dev 17 3112–26 Occurrence Handle14681207 Occurrence Handle10.1101/gad.1158703 Occurrence Handle1:CAS:528:DC%2BD2cXhs1Sgsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  25. SR Hingorani L Wang AS Multani C Combs TB Deramaudt RH Hruban et al. (2005) ArticleTitleTrp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice Cancer Cell 7 469–83 Occurrence Handle15894267 Occurrence Handle10.1016/j.ccr.2005.04.023 Occurrence Handle1:CAS:528:DC%2BD2MXkslyitLk%3D

    Article  PubMed  CAS  Google Scholar 

  26. CJ Sherr (2000) ArticleTitleCell cycle control and cancer Harvey Lect 96 73–92 Occurrence Handle12200872

    PubMed  Google Scholar 

  27. C Caldas SA Hahn LT Da Costa MS Redston M Schutte AB Seymour et al. (1994) ArticleTitleFrequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma Nat Genet 8 27–32 Occurrence Handle7726912 Occurrence Handle10.1038/ng0994-27 Occurrence Handle1:CAS:528:DyaK2cXmtVajsL0%3D

    Article  PubMed  CAS  Google Scholar 

  28. M Schutte RH Hruban J Geradts R Maynard W Hilgers SK Rabindran et al. (1997) ArticleTitleAbrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas Cancer Res 57 3126–30 Occurrence Handle9242437 Occurrence Handle1:CAS:528:DyaK2sXkvFKru78%3D

    PubMed  CAS  Google Scholar 

  29. T Ueki M Toyota T Sohn CJ Yeo JP Issa RH Hruban et al. (2000) ArticleTitleHypermethylation of multiple genes in pancreatic adenocarcinoma Cancer Res 60 1835–9 Occurrence Handle10766168 Occurrence Handle1:CAS:528:DC%2BD3cXisVynur4%3D

    PubMed  CAS  Google Scholar 

  30. Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, et al. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 58:4740–4

  31. C Rosty J Geradts N Sato RE Wilentz H Roberts T Sohn et al. (2003) ArticleTitlep16 inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis Am J Surg Pathol 27 1495–501 Occurrence Handle14657708 Occurrence Handle10.1097/00000478-200312000-00001

    Article  PubMed  Google Scholar 

  32. Hustinx SR, Hruban RH, Leoni LM, Iacobuzio-Donahue C, Cameron JL, Yeo CJ, et al. Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: a potential new target for therapy. Cancer Biol Ther 2005;4

  33. SR Hustinx LM Leoni CJ Yeo PN Brown M Goggins SE Kern et al. (2005) ArticleTitleConcordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion Mod Pathol 18 959–63 Occurrence Handle15832197 Occurrence Handle10.1038/modpathol.3800377 Occurrence Handle1:CAS:528:DC%2BD2MXltlCitL8%3D

    Article  PubMed  CAS  Google Scholar 

  34. MS Redston C Caldas AB Seymour RH Hruban L Da Costa CJ Yeo et al. (1994) ArticleTitlep53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions Cancer Res 54 3025–33 Occurrence Handle8187092 Occurrence Handle1:CAS:528:DyaK2cXksFWiur4%3D

    PubMed  CAS  Google Scholar 

  35. IO Baas JW Mulder GJ Offerhaus B Vogelstein SR Hamilton (1994) ArticleTitleAn evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms J Pathol 172 5–12 Occurrence Handle7931827 Occurrence Handle10.1002/path.1711720104 Occurrence Handle1:CAS:528:DyaK2cXmvFKnt7g%3D

    Article  PubMed  CAS  Google Scholar 

  36. A Maitra NV Adsay P Argani C Iacobuzio-Donahue A De Marzo JL Cameron et al. (2003) ArticleTitleMulticomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray Mod Pathol 16 902–12 Occurrence Handle13679454 Occurrence Handle10.1097/01.MP.0000086072.56290.FB

    Article  PubMed  Google Scholar 

  37. SA Hahn M Schutte AT Hoque CA Moskaluk LT da Costa E Rozenblum et al. (1996) ArticleTitleDPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 Science 271 350–3 Occurrence Handle8553070 Occurrence Handle10.1126/science.271.5247.350 Occurrence Handle1:CAS:528:DyaK28XlsFartg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  38. RE Wilentz CA Iacobuzio-Donahue P Argani DM McCarthy JL Parsons GJ Yeo et al. (2000) ArticleTitleLoss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression Cancer Res 60 2002–6 Occurrence Handle10766191 Occurrence Handle1:CAS:528:DC%2BD3cXisVymsr0%3D

    PubMed  CAS  Google Scholar 

  39. AD D'Andrea M Grompe (2003) ArticleTitleThe Fanconi anaemia/BRCA pathway Nat Rev Cancer 3 23–34 Occurrence Handle12509764 Occurrence Handle10.1038/nrc970

    Article  PubMed  Google Scholar 

  40. MS van der Heijden JR Brody E Gallmeier SC Cunningham DA Dezentje D Shen et al. (2004) ArticleTitleFunctional defects in the Fanconi anemia pathway in pancreatic cancer cells Am J Pathol 165 651–7 Occurrence Handle15277238 Occurrence Handle1:CAS:528:DC%2BD2cXmvFWjs7o%3D

    PubMed  CAS  Google Scholar 

  41. AP Klein RH Hruban KA Brune GM Petersen M Goggins (2001) ArticleTitleFamilial pancreatic cancer Cancer J 7 266–73 Occurrence Handle11561603 Occurrence Handle1:STN:280:DC%2BD3MrhtlOjtw%3D%3D

    PubMed  CAS  Google Scholar 

  42. M Goggins RH Hruban SE Kern (2000) ArticleTitleBRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications Am J Pathol 156 1767–71 Occurrence Handle10793087 Occurrence Handle1:CAS:528:DC%2BD3cXjslKksrc%3D

    PubMed  CAS  Google Scholar 

  43. GA Griffin RH Hruban LA Morsberger T Ellingham PP Long EM Jaffee et al. (1995) ArticleTitleConsistent chromosome abnormalities in adenocarcinoma of the pancreas Cancer Res 55 2394–9 Occurrence Handle7757992 Occurrence Handle1:CAS:528:DyaK2MXlvFeqs70%3D

    PubMed  CAS  Google Scholar 

  44. CA Iacobuzio-Donahue MS van der Heijden MR Baumgartner WJ Troup JM Romm K Doheny et al. (2004) ArticleTitleLarge-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss Cancer Res 64 871–5 Occurrence Handle14871814 Occurrence Handle10.1158/0008-5472.CAN-03-2756 Occurrence Handle1:CAS:528:DC%2BD2cXhtFCgtb4%3D

    Article  PubMed  CAS  Google Scholar 

  45. J Luttges H Galehdari V Brocker I Schwarte-Waldhoff D Henne-Bruns G Kloppel et al. (2001) ArticleTitleAllelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis Am J Pathol 158 1677–83 Occurrence Handle11337365 Occurrence Handle1:CAS:528:DC%2BD3MXktVOitr0%3D

    PubMed  CAS  Google Scholar 

  46. M Yamano H Fujii T Takagaki N Kadowaki H Watanabe T Shirai (2000) ArticleTitleGenetic progression and divergence in pancreatic carcinoma Am J Pathol 156 2123–33 Occurrence Handle10854233 Occurrence Handle1:CAS:528:DC%2BD3cXksFSqsrw%3D

    PubMed  CAS  Google Scholar 

  47. NT van Heek AK Meeker SE Kern CJ Yeo KD Lillemoe JL Cameron et al. (2002) ArticleTitleTelomere shortening is nearly universal in pancreatic intraepithelial neoplasia Am J Pathol 161 1541–7 Occurrence Handle12414502 Occurrence Handle1:CAS:528:DC%2BD38XptV2gtrs%3D

    PubMed  CAS  Google Scholar 

  48. D Gisselsson (2003) ArticleTitleChromosome instability in cancer: how, when, and why? Adv Cancer Res 87 1–29 Occurrence Handle12641272 Occurrence Handle10.1016/S0065-230X(03)87293-7 Occurrence Handle1:CAS:528:DC%2BD3sXjsl2nsb8%3D

    Article  PubMed  CAS  Google Scholar 

  49. AP Feinberg (2004) ArticleTitleThe epigenetics of cancer etiology Semin Cancer Biol 14 427–32 Occurrence Handle15489135 Occurrence Handle10.1016/j.semcancer.2004.06.005 Occurrence Handle1:CAS:528:DC%2BD2cXos1Kkt7o%3D

    Article  PubMed  CAS  Google Scholar 

  50. SB Baylin JG Herman (2000) ArticleTitleDNA hypermethylation in tumorigenesis: epigenetics joins genetics Trends Genet 16 168–74 Occurrence Handle10729832 Occurrence Handle10.1016/S0168-9525(99)01971-X Occurrence Handle1:CAS:528:DC%2BD3cXit1Sqsbg%3D

    Article  PubMed  CAS  Google Scholar 

  51. N Fukushima N Sato T Ueki C Rosty KM Walter RE Wilentz et al. (2002) ArticleTitleAberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma Am J Pathol 160 1573–81 Occurrence Handle12000709 Occurrence Handle1:CAS:528:DC%2BD38XksVKrtL4%3D

    PubMed  CAS  Google Scholar 

  52. M Jansen N Fukushima C Rosty K Walter R Altink TV Heek et al. (2002) ArticleTitleAberrant methylation of the 5′-CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanlNs Cancer Biol Ther 1 293–6 Occurrence Handle12432281 Occurrence Handle1:CAS:528:DC%2BD3sXlt1Whug%3D%3D

    PubMed  CAS  Google Scholar 

  53. M Goggins (2005) ArticleTitleMolecular markers of early pancreatic cancer J Clin Oncol 23 4524–31 Occurrence Handle16002843 Occurrence Handle10.1200/JCO.2005.19.711 Occurrence Handle1:CAS:528:DC%2BD2MXnsl2ksL4%3D

    Article  PubMed  CAS  Google Scholar 

  54. WM Klein RH Hruban AJ Klein-Szanto RE Wilentz (2002) ArticleTitleDirect correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression Mod Pathol 15 441–7 Occurrence Handle11950919 Occurrence Handle10.1038/modpathol.3880544

    Article  PubMed  Google Scholar 

  55. AV Biankin JG Kench AL Morey CS Lee SA Biankin DR Head et al. (2001) ArticleTitleOverexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia Cancer Res 61 8830–7 Occurrence Handle11751405 Occurrence Handle1:CAS:528:DC%2BD38Xht1OmtA%3D%3D

    PubMed  CAS  Google Scholar 

  56. S Gansauge F Gansauge M Ramadani H Stobbe B Rau N Harada et al. (1997) ArticleTitleOverexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis Cancer Res 57 1634–7 Occurrence Handle9134998 Occurrence Handle1:CAS:528:DyaK2sXjtFelsL4%3D

    PubMed  CAS  Google Scholar 

  57. V Miyamoto A Maitra B Ghosh U Zechner P Argani CA Iacobuzio-Donahue et al. (2003) ArticleTitleNotch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis Cancer Cell 3 565–76 Occurrence Handle12842085 Occurrence Handle10.1016/S1535-6108(03)00140-5 Occurrence Handle1:CAS:528:DC%2BD3sXltlSmsLw%3D

    Article  PubMed  CAS  Google Scholar 

  58. DM Berman SS Karhadkar A Maitra R Montes De Oca MR Gerstenblith K Briggs et al. (2003) ArticleTitleWidespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours Nature 425 846–51 Occurrence Handle14520411 Occurrence Handle10.1038/nature01972 Occurrence Handle1:CAS:528:DC%2BD3sXotlWqsLc%3D

    Article  PubMed  CAS  Google Scholar 

  59. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Castillo CF, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003, doi:10.1038/nature02009

  60. NB Prasad AV Biankin N Fukushima A Maitra S Dhara AG Elkahloun et al. (2005) ArticleTitleGene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells Cancer Res 65 1619–26 Occurrence Handle15753353 Occurrence Handle10.1158/0008-5472.CAN-04-1413 Occurrence Handle1:CAS:528:DC%2BD2MXitVOjs74%3D

    Article  PubMed  CAS  Google Scholar 

  61. J Taipale PA Beachy (2001) ArticleTitleThe Hedgehog and Wnt signalling pathways in cancer Nature 411 349–54 Occurrence Handle11357142 Occurrence Handle10.1038/35077219 Occurrence Handle1:CAS:528:DC%2BD3MXktVSjsrw%3D

    Article  PubMed  CAS  Google Scholar 

  62. SC Abraham TT Wu RH Hruban JH Lee CJ Yeo K Conlon et al. (2002) ArticleTitleGenetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beat-catenin pathway Am J Pathol 160 953–62 Occurrence Handle11891193 Occurrence Handle1:CAS:528:DC%2BD38XisVemt78%3D

    PubMed  CAS  Google Scholar 

  63. SC Abraham DS Klimstra RE Wilentz CJ Yeo K Conlon M Brennan et al. (2002) ArticleTitleSolid pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations Am J Pathol 160 1361–9 Occurrence Handle11943721 Occurrence Handle1:CAS:528:DC%2BD38XjsFGjtrc%3D

    PubMed  CAS  Google Scholar 

  64. SC Abraham TT Wu DS Klimstra LS Finn JH Lee CJ Yeo et al. (2001) ArticleTitleDistinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas: frequent alterations in the APC/beta-catenin pathway and chromosome 11p Am J Pathol 159 1619–27 Occurrence Handle11696422 Occurrence Handle1:CAS:528:DC%2BD3MXoslartL0%3D

    PubMed  CAS  Google Scholar 

  65. ON Tucker AJ Dannenberg EK Yang F Zhang L Teng JM Daly et al. (1999) ArticleTitleCyclooxygenase-2 expression is up-regulated in human pancreatic cancer Cancer Res 59 987–90 Occurrence Handle10070951 Occurrence Handle1:CAS:528:DyaK1MXhslemtLw%3D

    PubMed  CAS  Google Scholar 

  66. Wu KK (2005) ArticleTitleControl of cyclooxygenase-2 transcriptional activation by pro-inflammatory mediators Prostaglandins Leukot Essent Fatty Acids 72 89–93 Occurrence Handle10.1016/j.plefa.2004.11.001

    Article  Google Scholar 

  67. S Zha V Yegnasubramanian WG Nelson WB Isaacs AM De Marzo (2004) ArticleTitlecyclooxygenases in cancer: progress and perspective Cancer Lett 215 1–20 Occurrence Handle15374627 Occurrence Handle10.1016/j.canlet.2004.06.014 Occurrence Handle1:CAS:528:DC%2BD2cXnslGhsr0%3D

    Article  PubMed  CAS  Google Scholar 

  68. A Maitra R Ashfaq CR Gunn A Rahman CJ Yeo TA Sohn et al. (2002) ArticleTitleCyclooxygenase-2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging Am J Clin Pathol 118 194–201 Occurrence Handle12162677 Occurrence Handle10.1309/TPG4-CK1C-9V8V-8AWC Occurrence Handle1:CAS:528:DC%2BD38XmsVWrsLw%3D

    Article  PubMed  CAS  Google Scholar 

  69. R Albazaz CS Verbeke SH Rahman MJ McMahon (2005) ArticleTitleCyclooxygenase-2 expression associated with severity of PanIN lesions: a possible link between chronic pancreatitis and pancreatic cancer Pancreatology 5 361–9 Occurrence Handle15980665 Occurrence Handle10.1159/000086536 Occurrence Handle1:CAS:528:DC%2BD2MXntFSmsb0%3D

    Article  PubMed  CAS  Google Scholar 

  70. GM Sclabas T Uwagawa C Schmidt KR Hess DB Evans JL Abbruzzese et al. (2005) ArticleTitleNuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin Cancer 103 2485–90 Occurrence Handle15861417 Occurrence Handle10.1002/cncr.21075 Occurrence Handle1:CAS:528:DC%2BD2MXlvVCktLs%3D

    Article  PubMed  CAS  Google Scholar 

  71. T Shiomi Y Okada (2003) ArticleTitleMT1-MMP and MMP-7 in invasion and metastasis of human cancers Cancer Metastasis Rev 22 145–52 Occurrence Handle12784993 Occurrence Handle10.1023/A:1023039230052 Occurrence Handle1:CAS:528:DC%2BD3sXis1Cjt7s%3D

    Article  PubMed  CAS  Google Scholar 

  72. T Vargo-Gogola B Fingleton HC Crawford LM Matrisian (2002) ArticleTitleMatrilysin (matrix metalloproteinase-7) selects for apoptosis-resistant mammary cells in vivo Cancer Res 62 5559–63 Occurrence Handle12359768 Occurrence Handle1:CAS:528:DC%2BD38Xnsl2lsbw%3D

    PubMed  CAS  Google Scholar 

  73. HC Crawford CR Scoggins MK Washington LM Matrisian SD Leach (2002) ArticleTitleMatrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas J Clin Invest 109 1437–44 Occurrence Handle12045257 Occurrence Handle10.1172/JCI200215051 Occurrence Handle1:CAS:528:DC%2BD38XktlWlu70%3D

    Article  PubMed  CAS  Google Scholar 

  74. P Argani C Rosty RE Reiter RE Wilentz SR Murugesan SD Leach et al. (2001) ArticleTitleDiscovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma Cancer Res 61 4320–4 Occurrence Handle11389052 Occurrence Handle1:CAS:528:DC%2BD3MXktlSqurs%3D

    PubMed  CAS  Google Scholar 

  75. CA Iacobuzio-Donahue A Maitra GL Shen-Ong T van Heek R Ashfaq R Meyer et al. (2002) ArticleTitleDiscovery of novel tumor markers of pancreatic cancer using global gene expression technology Am J Pathol 160 1239–49 Occurrence Handle11943709 Occurrence Handle1:CAS:528:DC%2BD38XjsFGjsbY%3D

    PubMed  CAS  Google Scholar 

  76. CA Iacobuzio-Donahue A Maitra M Olsen AW Lowe NT van Heek C Rosty et al. (2003) ArticleTitleExploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays Am J Pathol 162 1151–62 Occurrence Handle12651607 Occurrence Handle1:CAS:528:DC%2BD3sXjtVemtL0%3D

    PubMed  CAS  Google Scholar 

  77. CA Iacobuzio-Donahue R Ashfaq A Maitra NV Adsay GL Shen-Ong K Berg et al. (2003) ArticleTitleHightly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparision of the transcription profiles obtained from three major technologies Cancer Res 63 8614–22 Occurrence Handle14695172 Occurrence Handle1:CAS:528:DC%2BD3sXhtVSqtLjK

    PubMed  CAS  Google Scholar 

  78. H Han DJ Bearss LW Browne R Calaluce RB Nagle DD Von Hoff (2002) ArticleTitleIdentification of differentially expressed genes in pancreatic cancer cells using cDNA microarray Cancer Res 62 2890–6 Occurrence Handle12019169 Occurrence Handle1:CAS:528:DC%2BD38XjvFSmt7c%3D

    PubMed  CAS  Google Scholar 

  79. CD Logsdon DM Simeone C Binkley T Arumugam JK Greenson TJ Giordano et al. (2003) ArticleTitleMolecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer Cancer Res 63 2469–57

    Google Scholar 

  80. P Argani C Iacobuzio-Donahue B Ryu C Rosty M Goggins RE Wilentz et al. (2001) ArticleTitleMesothelin is overexpressed in the vast majority of ductal adenocarinomas of the pancreas: identification of a new pancreatic cancer market by serial analysis of gene expression (SAGE) Clin Cancer Res 7 3862–8 Occurrence Handle11751476 Occurrence Handle1:CAS:528:DC%2BD38XltV2qsA%3D%3D

    PubMed  CAS  Google Scholar 

  81. MF Offield TL Jetton PA Labosky M Ray RW Stein MA Magnuson et al. (1996) ArticleTitlePDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum Development 122 983–95 Occurrence Handle8631275 Occurrence Handle1:CAS:528:DyaK28XhvVOruro%3D

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Ross Bldg 632, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD, 21205, USA

    Georg Feldmann, Robert Beaty, Ralph H. Hruban & Anirban Maitra

  2. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Ross Bldg 632, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore, MD, 21205, USA

    Ralph H. Hruban & Anirban Maitra

  3. McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Anirban Maitra

Authors
  1. Georg Feldmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Beaty
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ralph H. Hruban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anirban Maitra
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Feldmann, G., Beaty, R., Hruban, R. et al. Molecular genetics of pancreatic intraepithelial neoplasia. J Hepatobiliary Pancreat Surg 14, 224–232 (2007). https://doi.org/10.1007/s00534-006-1166-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00534-006-1166-5

Keywords

Search

Navigation